Gliederung

Objective: Recent studies showed that human glioma cells secrete glutamate, by which their growth was increased. This proliferation facilitation was explained by a glioma-brain interaction. Blockade of NMDA-receptors led to a reduction of glioma growth. In this study the expression of glutamate and NMDA receptors in gliomas and their vicinity is analyzed in order to see if there is a correlation with the tumor’s WHO-grade.

Methods: Immunohistochemical staining and semiquantative analysis were done in specimens of human gliomas. Normal brain tissue from autopsies served as a control. Antibodies were anti-Glutamate and anti-NMDAR1. The semiquantative analysis of immunopositivity was done macro- and microscopically by two independent investigators.

Results: Human low-grade gliomas and glioblastomas were investigated. Whereas low-grade gliomas almost never showed an expression of tumor cell associated glutamate, we found this neurotransmitter regularly positive within glioblastomas. Additionally, glutamate producing cells with a massive intracellular glutamate load and no other cytoplasmic components were only observed in the group of glioblastomas. The expression of glutamate was stronger than the expression of NMDAR1, as we did not find NMDAR1 in low-grade gliomas or normal brain controls. Human glioblastomas that invaded the cortical layers induced a strong fibrillary expression of NMDAR1 that morphologically resembled neuronal processes. Although not always positive, glioblastomas were observed in which NMDAR1 was expressed in a clearly tumor cell-associated fashion. This was not seen in the low-grade glioma group.

Conclusions: We could show that there is an increased density of glutamate-positivity in highly malignant gliomas compared to normal brain tissue. There were several specimens in which a pronounced intracellular accumulation of glutamate-vesicles could be seen. These findings strengthen the idea that glioma cells are able to secrete glutamate. By the mechanism of neuronal excitotoxicity this might lead to further proliferation facilitation. This is supported by an increased NMDAR1-positivity at the brain-tumor-interface and in the near vicinity of the glioma. A further interesting finding was an up-regulated glutamate-positivity in vascular walls of tumor blood vessels of grade IV gliomas.